What is remdesivir and will it work?

Why is there so much hype for medications that ultimately turn out to be ineffective?

It seems that every week there is a new drug that is being hyped as a “game changer” in treating COVID-19. This drug is touted to be the solution to this great crisis and everyone gets excited for a few days only to be disappointed later when it is discovered that it wasn’t the magic bullet it was hyped up to be. Why does this keep happening? Why can’t they get it right? This is the nature of the beast when it comes to medical research. The world is a complicated place and rarely are simple solutions the right ones. This is even more true with a pandemic such as COVID-19 which has spread so fast and is causing levels of alarm and anxiety not seen in 100 years. Unfortunately, and social media isn’t able to communicate the complexity and nuance.

The way medical research typically progresses is not amenable to the 24 hours cable news cycle or a Facebook timeline but is essential to finding the safest and most effective treatments. What typically happens is that small studies are done in the lab and in animals showing a plausible reason to believe that a specific chemical would work for a specific disease. There will then be small studies in humans to show safety and effectiveness. The problem is that the smaller the study the more likely a positive result will be due to chance and not due to a true benefit of the drug. These small studies then may show benefit but this could be due to statistical errors.

A necessary component of the scientific method which is often forgotten is the need to replicate results with more experiments in different contexts. With medical research this will eventually lead to larger and better designed studies. These are not done from the outset because there needs to be preliminary data justifying the huge expense of the larger studies. After the data from multiple large and small trials is combined conclusions can then be reached about the effectiveness of the drug.

The panic and anxiety of COVID-19 and the fact that we live in the cable news and internet age has created a perfect storm of hype and impatience. The news media (and even more so social media) reports positive results of these smaller studies but ignores or underplayes their uncertainty. Everyone then becomes overly optimistic. The smaller studies can also underplay the risks (as was seen with hydroxychloroquine).

This brings us to the latest hot topic drug – remdesivir. Remdesivir is a chemical that is incorporated into the viral RNA of the coronavirus when it replicates and inactivates it. At least that’s what happens in lab studies. In animal studies remdesivir decreased viral load and clinical symptoms with other coronavirus infections. This was all promising but we have been here before. It is frequent for drugs to be promising in the lab only to disappoint when they are tested in humans.

Because of the strange and unprecedented times we live in, remdesivir got hyped and demand shot up for its use. Normally the FDA does not allow drugs to be distributed unless they are proven safe and effective. In some cases, such as a pandemic, there will be an exception and the drug can be given on a compassionate use exemption. This was the case with remdesivir. There were stories of desperate families trying to get this drug on the shred of hope that it was beneficial. They could only get it from the pharmaceutical company based on this exemption. This led to a case series published in the New England Journal of Medicine. of patients who got the drug.

The problem is that this publication is a media show more than reliable science for This design cannot be relied upon to draw conclusions for multiple reasons. There was no control group which makes it vital that patient selection is unbiased and represents an average group of COVID-19 patients. This was not the case with this series. There is no documentation of how many patients applied. There is no data comparing characteristics of patients included in the study versus patients denied medication. Given lack of any control group, lack of transparency about this selection process is stunning. The manufacturer (Gilead) excluded many patients with a higher likelihood of dying. FDA regulations usually prevent pharmaceutical companies from so blatantly manipulating the data. There was one case where a patient was denied drug because he was too sick but then improved on his own and Gilead changed their mind and allowed the drug to be given. Yikes. There were several other serious design flaws that would probably have prevented a study like this from being published in any reputable medical journal at any other time (let alone the prestigious New England Journal of Medicine).

There was recent media buzz when Dr. Fauci reported preliminary results from the Adaptive COVID-19 Treatment Trial, or ACTT). It showed that patients who got the drug improved on average 4 days faster (15 vs 11d). The was a mortality benefit but this was not statistically significant. They have just finished the trial and the final publication is being worked on. Keep in mind, Dr. Fauci reported this from the oval office. Anything presented in the presence of politicians is a political move not a scientific one.

This trial will need to be put in the context of another recenta randomized, double blind placebo-controlled trial of 236 patients in China of remdesivir in severe COVID-19 looking for clinical improvement in disease severity or faster discharge. This trial design was excellent but ynfortunately they found no benefit of remdesivir in any measurements of clinical benefit or viral load.

This does not mean the remdesivir is not beneficial. The patients in these trials had severe disease. Since this drug blocks replication of the virus it may only be effective early on. Once the disease has become severe the horse is out of the barn and slowing down viral replication will not be expected to be beneficial. This is a similar story to what was seen with the influenza drug Tamiflu. It too is only beneficial when given early on and its benefits are not dramatic.

Unfortunately this is how things usually go. Early data shows promise and everyone gets excited but it usually comes from poor quality research. Subsequent data shows no benefit or a benefit that is not nearly as great as previously thought. I think this will be the case with remdesivir. It may be beneficial and we probably will use it but it will not be the magic bullet we all are hoping for. We’ll have to see the results of the ACTT. I am skeptical but there’s always hope.